Crystal engineering of the composition of pharmaceutical phases. Do
`pharmaceutical co-crystals represent a new path to improved medicines?
`
`Orn Almarsson*a and Michael J. Zaworotko*h
`~ TransForm Pharmaceuticals, Inc., 29 HartwellAvenue, Lexington, MA 02421, USA.
`E-mail: almarsson@tran,~’formpharma.com; Fax." +781 863 6519; Tel." +781 674 7894
`h Department of Chemistry, University of South Florida, SCA400, 4202 E. Fowler Avenue, Tampa, FL
`
`33620, USA. E-mail: xtal@u~’f.edu; Fax." +813 974 3203; Tel." +813 974 4129
`
`Received (in Columbia, MO, USA) 11th February 2004, Accepted 26th May 2004
`First published as an Advance Article on the web 5th August 2004
`
`The evolution of crystal engineering into a form of supramo-
`lecular synthesis is discussed in the context of problems and
`opportunities in the pharmaceutical industry. Specifically, it
`has become clear that a wide array of multiple component
`pharmaceutical phases, so called pharmaceutical co-crystals,
`can be rationally designed using crystal engineering, and the
`strategy affords new intellectual property and enhanced proper-
`ties for pharmaceutical substances.
`
`1 Introduction
`
`"Benzoic acid and other carboxylic acids have been sho~vn to be
`associated to double molecules in solution in certain solvents, such
`as benzene, chloroform, carbon tetrachloride and carbon dis-
`ulfide...Benzoic acid exists in the monomeric form in solution in
`acetone, acetic acid, ethyl ether, ethyl alcohol, ethyl acetate and
`phenol; in these solutions the single molecules are stabilized by
`hydrogen bond formation ~vith the solvent." (Linus Pauling in The
`Nature qf the Chemical Bond, 2nd edition, Cornell University
`Press, 1948.)
`
`Dr Orn Almarsson is senior director qf Pharmaceutical Chemistry
`
`at TransForm Pharmaceuticals, inc. Prior to joining TransForm in
`December qf 2000, he was a research jbllow in the department qf
`Pharmaceutical Research and Development at Merck Research
`
`Laboratories in West Point, Pennsylvania. He received his BS
`degree in chemistryj?om the University qf lceland in 1988 and his
`PhD in physical-organic chemistry ,/born the University qf Cal-
`~/brnia at Santa Barbara in 1994. His PhD thesis work, pe~/brmed
`
`under Prqf Thomas C. Bruice, is in the ,field qf bio-organic
`mechanisms qf nicotinamide co:/bctor redox reactions in dehy-
`drogenases and the mechanisms qf O 0 bond cleavage in
`peroxidase model ~systems. At TransForm, Dr Almarsson has
`jbcused on development and application qf high-throughput
`
`crystallization technologies jbr pharmaceutical compounds. His
`current work involves optimizing crystal jbrms jbr jbrmulation qf
`drug development candidates with the aim qf enhancing bio-
`pharmaceutical pe~/brmance and drug delivery properties.
`
`Dr Mike Zaworotko is Prq/bssor and Chair qf the Department qf
`Chemistry at the University qf South Florida, USF. He was born in
`Wales in 1956 and received his BSc and PhD degreesj?om imperial
`College (1977) and the University q/~4labama (1982), respectively.
`He joined USF in 1999. Current research interests include the
`jbllowing: crystal engineering, nanotechnology, supramolecular
`chemistry, X-ray crystallography. Particular emphasis is currently
`placed upon applications qf crystal engineering in the context qf
`nanoscale structures, magnetism, porosity and compositions qf
`active pharmaceutical ingredients. Dr Zaworotko has published
`over 210 peer reviewed papers and he currently serves on the
`editorial boards qf J. Chemical Crystallography and Crystal
`Growth & Design.
`
`In terms of intrinsic value, active pharmaceutical ingredients
`(API’s) are among the most valuable materials on the planet. It is
`therefore surprising that the grooving field of crystal engineeringI ~
`and its ability to produce ne~v and potentially valuable materials has
`only addressed API’s ~vithin the last t~vo years.4 9 Pharmaceuticals
`are generally comprised of an API, a formulation containing
`inactive ingredients as a carrier system, and a package for market
`performance and appeal. The vast majority of API’s occur as solids.
`Crystalline API’ s are strongly preferred due to their relative ease of
`isolation, the rejection of impurities inherent to the crystallization
`process and the physico-chemical stability that the crystalline solid
`state affords. The problems that arise ~vith the use of crystalline
`material are usually related to poor solubility properties and the
`existence of more than one crystalline form of an API. In terms of
`regulatory approval crystalline forms of an API have traditionally
`been limited to polymorphs, salts and stoichiometric solvates
`(pseudopolymorphs).1° Ho~vever, crystal engineering affords a
`paradigm for rapid development of a fourth class of API’s, that of
`pharmaceutical co-crystals.
`Crystal engineering can be defined as application of the concepts
`of supramolecular chemistry to the solid state ~vith particular
`emphasis upon the idea that crystalline solids are de jbcto
`manifestations of self-assembly. Crystal structures can therefore be
`regarded as the result of a series of ~veak but directional molecular
`recognition events. With understanding comes the possibility of
`design and it is the advent of supramolecular synthesisI ~ that
`facilitates the rational design of ne~v structures and compositions.
`The roots of crystal engineering can be traced at least as far back as
`the 1930’s, ~vhen Pauling defined the chemical bond in both
`covalent and noncovalent terms. 11 The term "crystal engineering"
`~vas coined by Pepinsky in 195512 but ~vas not implemented until
`Schmidt studied a series of solid state reactions in crystalline
`solids.1~ Indeed, solvent free synthesis continues to represent an
`active area of research in the context of crystal engineering.14,1~
`Based upon literature citations,~ it is apparent that crystal
`engineering enjoyed rapid gro~vth during the 1990’s, especially in
`terms of organic solids and metal-organic solids but also in terms of
`organometallic16 and inorganic structures.17
`What are pharmaceutical co-crystals? Herein ~ve define pharma-
`ceutical co-crystals as being a subset of a broader group of multi-
`component crystals that also includes salts, solvates (pseudopoly-
`morphs), clathrates, inclusion crystals and hydrates. In a
`supramolecular context, solvates and pharmaceutical co-crystals
`are related to one another in that at least t~vo components of the
`crystal interact by hydrogen bonding and, possibly, other non-
`covalent interactions rather than by ion-pairing. Neutral com-
`pounds and salt forms alike have the potential to be solvated (i.e.
`interact ~vith solvent molecules) or co-crystallized (i.e. interact ~vith
`a co-crystal former). Solvate molecules and co-crystal formers can
`include organic acids or bases that remain in their neutral form
`~vithin the multi-component crystal. The primary difference is the
`physical state of the isolated pure components: if one component is
`a liquid at room temperature, the crystals are referred to as solvates;
`if both components are solids at room temperature, the products are
`
`Lupin Ex. 1033 (Page 1 of 8)
`
`

`

`referred to as co-crystals. While at first glance these differences
`may seem inconsequential, they have profound impact on the
`preparation, stability, and ultimately on developability of products.
`Furthermore, ~vhereas solvates are commonplace because they
`often occur as a serendipitous result of crystallization from
`solution, co-crystals, especially pharmaceutical co-crystals, repre-
`sent a relatively unexplored class of compounds. On the other hand,
`as ~vill become clear herein, pharmaceutical co-crystals can be
`rationally designed and there are many more potential co-crystal
`formers than there are solvents or counterions.
`The complex nature of APl structures means that they inherently
`contain exterior functional groups that engage in molecular
`recognition events. Indeed, it is the very presence of these
`functional groups that affords biological activity but also provides
`an ability to engage in more than one supramolecular event ~vith
`itself, a solvent molecule or co-crystal former, thereby forming
`polymorphs, solvates or co-crystals, respectively. It is important to
`note that there are t~vo basic types of molecular recognition that
`facilitate the formation of polymorphs, solvates and co-crystals.
`Functional groups that are self-complementary are capable of
`forming supramolecular homosynthons. For example, as revealed
`by Scheme la, carboxylic acid moieties and amide moieties can
`
`feature and conformational flexibility that are the primary driving
`forces for the existence of crystal polymorphism. It is therefore not
`surprising that it is ~vell and long documented that API’s can exist
`in several polymorphic, solvated and/or hydrated forms.I°,18 This
`tendency for polymorphism represents both a problem and an
`opportunity in pharmaceutical research. Lack of reliability of
`manufacturing and physical (and sometimes chemical) instability
`of a given polymorph can be an issue for a drug developer, ~vhile a
`novel polymorph in the hands of a competitor can provide options
`for generic pharmaceutical competition.
`We shall focus upon polymorphism from a supramolecular
`perspective ~vith emphasis upon t~vo functional groups that are
`commonly encountered in API’s: carboxylic acids and amides.
`
`2.1 Structures in which carboxylic acids are involved in
`self-organization.
`
`Carboxylic acid moieties represent perhaps the longest and most
`~videly studied functional group in terms of our understanding of
`hydrogen bonding in both solution and the solid state.ll In the
`context of crystal structures, carboxylic acids exhibit a remarkable
`range of diversity in their supramolecular chemistry and this in turn
`leads to observation of polymorphs in even the most simple of
`chemical structures. There are t~vo primary modes for carboxylic
`acids to self-organize in the form of supramolecular homo synthons:
`the dimer and the catemer. Such "supramolecular isomerism" is the
`origin of polymorphism exhibited by the t~vo polymorphs of
`chloroacetic acid (Fig. 1). Fig. 1 a illustrates the dimer motif ~vhich
`
`Scheme 1 The formation of supramolecular synthons between acids and
`anaides: (a) supramaolecular homosynthons as exhibited by acid acid and
`anaide anaide dinaers; (b) supramolecul~x heterosynthons as exhibited by
`acid amide rfimers.
`
`form homodimers via a t~vo-point donor-acceptor molecular
`recognition path. Ho~vever, it is also possible for functional groups
`to engage ~vith a different but complementary functional group, as
`noted by Pauling. Indeed, carboxylic acids and amides are
`complementary ~vith each other and can interact through formation
`of a supramolecular heterosynthon (Scheme lb). This particular
`motif has been studied for some time in the context of co-
`
`Crystals. 18
`In this contribution ~ve detail the current and potential impact of
`crystal engineering on our understanding of polymorphs, solvates
`and co-crystals ~vith particular emphasis upon API’s. Carboxylic
`acid and amide moieties are ~videly encountered in API’s and
`studied in model compounds. They ~vill therefore be used
`extensively in this contribution even though it should be re-
`membered that they represent just a microcosm of the functional
`group diversity that exists in API’s.
`
`2 Crystal engineering in the context of
`polymorphs
`
`"A solid crystalline phase of a given compound resulting from the
`possibility of at least t~vo different arrangements of the molecules
`of that compound in the solid state" (W.C. McCrone inPhysics and
`Chemistry q~’the Organic Solid State, Vol II, Wiley Interscience,
`Ne~v York, 725 726, 1965.)
`McCrone’s definition of a polymorph as presented above is
`particularly appropriate in the context of drugs, since the existence
`of highly functional API’s invites multiple modes of self-
`organization and amounts to promiscuity in self-assembly. It is this
`
`Fig. 1 The self-organization modes seen in the two reported polymorphs of
`chloroacetic acid: (a) centrosymmetric dimer; (b) catemer motif, which
`leads to a tetrameric assembly.
`
`occurs in one polymorph19 ~vhereas Fig. lb presents the second
`form, in ~vhich a catemer supramolecular synthon results in the
`formation of a tetrameric supramolecular assembly5° It should be
`noted that carboxylic acid polymorphs are not al~vays a con-
`sequence of isomerism in supramolecular homosynthons. For
`example, they can result from factors such as different crystal
`packing arrangements of dimer motifs or, if appropriate, torsional
`flexibility, ~vhich can afford conformational polymorphism51
`Nevertheless, there are other simple carboxylic acids that exhibit
`polymorphism because of dimer/catemer supramolecular isomer-
`ism (e.g. hydroxybenzoic acid,~ oxalic acid~3 and tetrolic
`acid24).
`The stoW does not end there: ~vhereas there are over 4000 entries
`in the Cambridge Structural Database25 (CSD) of crystal structures
`in ~vhich at least one carboxylic acid moiety is present, 1179 exhibit
`the dimer motif (29.4%) and only 86 exhibit the catemer motif
`(2.1%). In other ~vords, the formation of supramolecular homosyn-
`thons is not the dominant supramolecular event in the solid state
`even if it might be in solution. An analysis of the remaining
`carboxylic acid containing crystal structures reveals that they
`typically form supramolecular structures that involve a carboxylic
`acid and a different functional group, i.e. they form supramolecular
`heterosynthons. The ability of a molecule to engage in either
`supramolecular homosynthons or supramolecular heterosynthons
`represents another avenue for the existence of polymorphism.
`
`Lupin Ex. 1033 (Page 2 of 8)
`
`

`

`Polymorphism in molecules ~vhich contain multiple functional
`groups is exemplified by Fig. 2, ~vhich presents the monoclinic and
`
`Fig. 2 The ruonoclinic (a) mad triclinic (b) forms of 2-(2-ruethyl-
`3-chluroanilino)-nicotinic acid, an analgesic/anti-inflaruruatory ruolecule.
`
`triclinic forms of 2-(2-methyl-3-chloroanilino)-nicotinic acid,26 a
`molecule that exhibits analgesic and anti-inflammatory properties.
`Fig. 2 reveals that 2-(2-methyl-3-chloroanilino)-nicotinic acid can
`self-organize via either supramolecular homosynthons or supramo-
`lecular heterosynthons: (a) generation of head-to-tail chains
`sustained by a carboxylic acid pyridine supramolecular heterosyn-
`thon; (b) formation of centrosymmetric dimers sustained by the
`carboxylic acid supramolecular homosynthon.
`It is important to emphasize the distinction bet~veen supramo-
`lecular homosynthons and supramolecular heterosynthons since the
`latter represent a possible entry into the realm of multiple-
`component crystals and a diverse range of compositions of matter
`and physical properties. That carboxylic acids represent such a
`large subset of the CSD makes it possible to ask an important
`question: are supramolecular heterosynthons not just rational but
`also predictable’? In the context of the pyridine~zarboxylic
`supramolecular heterosynthon the CSD reveals that there are 424
`compounds that contain both a carboxylic acid and an aromatic
`nitrogen base. 198 of these compounds (46.7%) exhibit the
`supramolecular heterosynthon rather than one of the carboxylic
`acid supramolecular homosynthons (Scheme 2). When one con-
`siders that many of the compounds in this dataset contain multiple
`functional groups this is a remarkably high rate of occurence.
`
`Fig. 3 The self-organization ruodes seen in two polyruorphs of chlur-
`oacetaruide: (a) centrosynmaetric dinaer that self-asserubles as 1-D tapes; (b)
`cateruer ruotif, which also forms 1-D tapes.
`
`polymorphic form of chloroacetamide that is the result of catemer
`motifs is illustrated in Fig. 3b. It reveals that the superstructure is
`also that of a tape. The t~vo forms of chloroacetamide crystallize in
`the same space group ~vith almost identical cell parameters. This is
`an extremely unusual situation and is presumably related to the fact
`that the t~vo tapes are similar in terms of dimensions and exterior
`features.
`Chloroacetic acid and chloroacetamide serve as illustrations of
`ho~v even small molecules ~vith only one hydrogen bonding group
`can generate polymorphs based upon supramolecular isomerism. A
`similar analogy can be found in API’s that contain acid and amide
`moieties. Piracetam, a learning process drug, is an amide-
`containing API that exemplifies the type of polymolphism that
`occurs ~vhen supramolecular isomerism occurs in supramolecular
`homosynthons. There are three forms of Piracetam reported in the
`CSD.32,33 Two of these forms exist as tapes that are sustained by the
`amide homodimer and NH...O~2(carboxamide) hydrogen bonds
`(Fig. 4a).32 The third form is sustained by catemer chains that are
`crosslinked by N H...O C(carboxamide) hydrogen bonds (Fig.
`4b).33 The superstructure can therefore be described as hydrogen
`bonded sheets.
`
`~, homosynthon
`
`~:s,
`
`b. heterosynthon
`
`Scheme 2 The horuosynthon vs. heterosynthon ruotifs observed in crystal
`structures of corupounds in which both c~xboxylic acids and pyridine
`ruoieties are present. The heterosynthon doruinates, occurring in 119/245
`crystal structures whereas the horuosynthon occurs in only 10 crystal
`structures.
`
`2.2 Structures in which primary amides are involved in
`self-organization
`
`Primary amides are also ~vell represented in the CSD, ~vith 1152
`entries. The dominant supramolecular homosynthon is the cen-
`trosymmetric dimer as presented in Scheme 1. This homosynthon
`contains complementary hydrogen bond donors and acceptors and
`is capable of further self-assembly, thereby generating supramo-
`lecular tapes or sheets. Fig. 3a illustrates ho~v chloroacetamide
`forms a tape net~vork based upon self-organization of homo-
`dimers.27 3o Interestingly, chloroacetamide also exhibits polymor-
`phism and for the same fundamental reason as chloroacetic acid: it
`exhibits a catemer structure as ~vell as a homodimer structure.31 The
`
`Fig. 4 The network structures formed by Piracetaru: (a) horuodiruers forru
`supraruolecular tapes two forrus; (b) 1-D chains sustained by the cateruer
`ruotif are found in the third form.
`
`To summarize the points made thus far:
`¯ Single component crystals that contain carboxylic acid or
`amide moieties are prone to polymorphism even if only one
`hydrogen bonding moiety is present and supramolecular homosyn-
`thons are the primary molecular recognition events.
`¯ In the case of APl’s, the situation is further complicated by the
`presence of additional hydrogen bonding moieties, ~vhich can lead
`to the formation of supramolecular heterosynthons.
`
`Lupin Ex. 1033 (Page 3 of 8)
`
`

`

`favored over the parent homosynthons. Aci~pyridine supramo-
`lecular heterosynthons, a subset of the acid aromatic amine set
`described earlier, occur in 119 of the 245 crystal structures that
`contain both functional groups. Remarkably, only 10 of these 245
`structures contain acid acid homosynthons (Scheme 2).
`Representative examples of co-crystals that are sustained by the
`pyridine~zarboxylic acid supramolecular synthon are presented in
`Fig. 6. Maleic acid : 4,4’-bipyridine forms a discrete 2:1 adduct42
`
`Fig. 6 Two exaruples of co-crystal structures forrued by the acid pyridine
`supraruolecular heterosynthon: (a) rualeic acid: 4,4’-bipyridine; (b) furuaric
`acid : 4,4~-bipyridine.
`
`~vhereas fumaric acid : 4,4’-bipyridine forms in 1:1 stoichiometry
`and thereby generates a 1-D chain.42
`
`3.2 Functional co-crystals
`
`Examples of co-crystals have existed in conductive organic
`crystals, non-linear optical crystals, dyes, pigments and agrochem-
`icals for some time43 but have only recently been applied to API’ s.
`Several recent papers emphasize the importance of understanding
`supramolecular heterosynthons in the synthesis of pharmaceutical
`co-crystals. For example, the ability to insert 4,4’-bipyridine and
`related molecules bet~veen the carboxylic acid dimers of aspirin,
`rac-ibuprofen, and rac-flurbiprofen ~vas recently reported.6 Fig. 7
`illustrates t~vo of these structures, ~vhich further demonstrate the
`ability of the pyridine carboxylic acid heterosynthon to compete
`~vith a carboxylic acid dimer homosynthon (Scheme 2).
`
`¯ Carboxylic acid and amide groups ~vere chosen as examples,
`because they are prevalent in the CSD and in API’s. Ho~vever, the
`points made thus far can be regarded as being generally relevant.
`For example, ~ve recently reported34 ho~v alcohol~ther heterosyn-
`thons can afford polymorphic forms of butylated hydroxy anisole,
`an antioxidant that is commonly used in solid dosage forms of
`API’s.35,3(~ The difference bet~veen the t~vo forms is striking: form
`l exists as the result of 4-fold helical chains: form II contains
`discrete hexamers.
`Ho~v one might exploit supramolecular heterosynthons for the
`crystal engineering of ne~v compositions of matter ~vill form the
`basis of the remainder of this contribution.
`
`3 Crystal engineering in the context of co-crystals
`
`"Supramolecular synthons are structural units ~vithin super-
`molecules that can be formed and/or assembled by kno~vn or
`conceivable synthetic operations involving intermolecular inter-
`actions". (Gautam R. Desiraju Angew. Chem. int. Ed. Engl., 34,
`2311, 1995.)
`Ho~v does one develop a strategy for the preparation of co-
`crystals’? Solvates are frequently encounted but are typically the
`result of serendipity rather than design and are often found as by-
`products of polymorph and salt screens. Co-crystals, on the other
`hand, are less ubiquitous but are more prone to rational design. Co-
`crystals have been prepared by melt-crystallization, by grinding37
`and by recrystallization from solvents.14,15 Pharmaceutical co-
`crystals have the potential to be much more useful in pharmaceuti-
`cal products than solvates or hydrates. First, the number of
`pharmaceutically acceptable solvents is very small. Secondly,
`solvents tend to be more mobile and have higher vapour pressures
`than small molecule co-crystal formers. It is not unusual to observe
`dehydration/desolvation ofhydrates/solvates in solid dosage forms,
`depending on storage conditions. Solvent loss frequently leads to
`amorphous compounds, ~vhich are generally less chemically stable
`and can crystallize into less soluble forms. In contrast to solvents,
`most co-crystal formers are unlikely to evaporate from solid dosage
`forms, making phase separation less likely.
`
`3.1 Co-crystals based upon acids or amides
`
`As suggested earlier, an effective approach to understanding and
`designing co-crystals is to apply the paradigm of supramolecular
`synthesis, in particular exploitation of supramolecular heterosyn-
`thons. The ubiquity of acids and amides in the CSD makes them
`appropriate foci for design and synthesis. Indeed, the aci~amide
`supramolecular heterosynthon illustrated in Scheme la has been
`exploited by several groups for the generation of CO-Crystals18,38~41
`and the CSD reveals that there are 118 crystal structures in ~vhich
`both an acid and an amide moiety are present. Remarkably, 58 of
`these structures exhibit the aci~amide supramolecular heterosyn-
`thon ~vhereas only 11 structures exhibit the acid homodimer and
`only 28 exhibit the amide homodimer. Fig. 5 presents t~vo
`
`Fig. 5 Two exmnples of co-crystals that ~xe sustained by the acid aruide
`supraruolecular heterosynthon: (a) succinic acid : benzaruide (1:2); (b) urea
`: glut~xic acid (1:1).
`
`prototypal examples of co-crystals that are sustained by the aci~
`amide supramolecular heterosynthon: succinic acid : benzamide1~
`and urea : glutaric acid.3~ Aci~amide supramolecular heterosyn-
`thons are not the only examples of robust heterosynthons that are
`
`Fig. 7 The 2:1 supraruolecul~x adducts formed by flurbiprofen and 4,4’-
`bipyrirfine (top) and 4,4’-dipyridylethane (bottoru). Siruilar structures occur
`for ibuprofen and aspirin.
`
`A second study focused on finding multiple solvates and co-
`crystals of carbamazepine.5 Carbamazepine represents an excellent
`test case since four polymorphs and t~vo solvates of carbamazepine
`have been reported in the literature. In all of the compounds for
`~vhich structural data is available, carbamazepine molecules
`crystallize as amide dimers (Fig. 8). The crystal structures illustrate
`that each dimer contains a peripheral H-bond donor and acceptor
`pair that is unsatisfied due to geometric constraints imposed by the
`drug molecule. Simple H-bond acceptor solvents like acetone and
`DMSO insert themselves to fill voids bet~veen the adjacent pairs of
`dimers. Multiple co-crystal formers having hydrogen bonding
`
`Lupin Ex. 1033 (Page 4 of 8)
`
`

`

`chains. In co-crystals ~vith piperazine, the acetaminophen forms
`head-to-head chains through IIIe. Each chain is joined to the next
`through a layer of piperazine molecules that interact through
`heterosynthons lllf and lllg. The paper also includes many
`solvates that ~vill not be revie~ved here, but their supramolecular
`synthons should also be applicable in the context of co-crystal
`design and formation.
`The analysis of molecules for complementarity of supramo-
`lecular synthons represents a valuable approach to screening that a
`kno~vledgeable scientist can exploit to narro~v the search for co-
`crystals. Ho~vever, an early study of 1:1 molecular complexes
`bet~veen the antibacterial agents trimethoprim (TMP) and sulfame-
`thoxypyridazine (SMP) highlights the need to explore the space
`beyond those leading to expected interactions.44 Each complex
`contains an 8-membered, hydrogen-bonded ring joining the t~vo
`molecules as sho~vn in Fig. 10. The specific ring structures formed
`
`Fig. 8 The czxbmnazepine dinaers that exist in all previously reported
`solvates and polyruorphs of carbaruazepine.
`
`groups like,vise insert themselves into the void, including saccharin
`and nicotinamide. The amide homosynthon can also be broken to
`form heterosynthon Ib. This ~vas achieved to form solvates ~vith
`acetic, formic, and butyric acids and co-crystals ~vith trimesic and
`nitroisophthalic acid. The crystal structures of the carbamazepine :
`saccharin co-crystal and the formic acid solvate are illustrated in
`Fig. 9.
`
`Fig. 9 Exaruples of the supraruolecular adducts formed in the crystal
`structures of co-crystals and solvates of carbaruazepine: (a) saccharin co-
`crystal; (b) carbaruazepine:formic acid solvate.
`
`A study of adducts of acetaminophen (paracetamol) ~vith ethers
`and amines provides additional examples of supramolecular
`synthons for co-crystal formation (Scheme 3).9 While supramo-
`
`Hs¢ ,H
`
`O
`
`H3C ,H
`
`H
`
`Scheme 3 The supraruolecular synthons observed in co-crystals of
`acetaruinophen (paracetaruol): IIIa-c occur in polyruorphs whereas IIId
`and IIIe occur in co-crystals.
`
`lecular homosynthon Ilia could have formed, both kno~vn forms of
`the pure material consist of linear head-to-tail chains held together
`through motif lllb; the chains are cross-linked through synthon
`lllc. The linear chain structure is preserved in co-crystals ~vith 4,4’-
`bipyridine, but the cross-linking interaction lllc is replaced by llld,
`in ~vhich the 4,4’-bipyridine is hydrogen bonded to the amide
`hydrogen. The chains remain cross-linked but only through pi-
`stacking interactions bet~veen 4,4’-bipyridine pairs on neighboring
`
`Fig. 10 The 8-ruerubered hydrogen-bonded ring that links antibacterial
`agents triruethopriru (TMP) and sulfaruethoxypyridazine (SMP).
`
`are not those that might have been predicted by inspection of the
`structures of the neutral molecules. Instead, the synthons are
`derived from the 2-aminopyridine of TMP and the z~vitterionic
`form of SMP involving the sulfonamide (pK, ~ 7) and pyridazine
`(pK, ~ 2). The z~vitterion is a thermodynamically unfavorable
`form of SMP in aqueous solution. This example of assembly
`through an unstable intermediate underscores the limitation of the
`approach of analyzing co-crystal formation solely on the basis of
`pK, arguments. A more comprehensive approach is needed. HT
`crystallization offers the possibility to uncover unexpected inter-
`actions by screening against a full library of pharmaceutically
`acceptable molecules instead of limiting the studies to co-crystal
`formers ~vith perceived complementarity.
`The more comprehensive approach to study expected and
`unexpected co-crystal formation events is high-throughput (HT)
`crystallization. The discovery of pharmaceutically acceptable co-
`crystals consisting of hydrogen-bonded trimers of t~vo molecules of
`cis-itraconazole, a triazole anti-fungal agent, and a molecule of a
`1,4-dicarboxylic acid resulting from a HT crystallization screen
`~vas recently reported.~ The crystal structure of the succinic acid co-
`crystal (Fig. 11) reveals a supramolecular heterosynthon bet~veen
`the triazole of each pair of drug molecule and carboxylic acid
`moieties on a single diacid molecule. The extended succinic acid
`molecule fills a pocket, ~vhile bridging the triazole groups. The
`interaction bet~veen the 1,4-diacid and the strongest base on
`itraconazole (piperazine) is not observed in the co-crystal structure.
`Other 1,4-diacids capable of extended (anti-) conformations also
`yielded co-crystals ~vith itraconazole, ~vhile co-crystals could not
`be made from maleic acid ~vith Z-regiochemistry, or from 1,3- or
`1,5-dicarboxylic acids. Hence, structural fit appears to be far more
`important than acid base strength complementarity for co-crystal-
`lization of itraconazole ~vith 1,4-dicarboxylic acids.
`The structures presented herein demonstrate that pharmaceutical
`co-crystals represent an interesting and emerging class of pharma-
`
`Lupin Ex. 1033 (Page 5 of 8)
`
`

`

`pharmaceutical co-crystals ~vould appear to be extremely large: one
`can easily envision thousands of possibilities for any given drug
`~vith at least t~vo synthons present in the molecule. Such diversity
`~vill probably be best addressed ~vith combinatorial methodologies,
`such as high-throughput crystallization.
`
`4.2 Can there be rational, directed design of
`pharmaceutical co-crystal phases?
`
`This is another question ~vhich relates to the prospect for design.
`Crystal structures are inherently unpredictable, but the interactions
`that occur prior to a crystal forming or grooving are predictable. An
`analogy can be dra~vn to salt selection,47,5° in ~vhich pK~ arguments
`are used to select acid base pairs that can be converted to salt
`compounds. The prediction of the proton transfer event is based on
`solution data, but the occurrence of a crystalline salt form cannot be
`predicted a priori. Based on the examples of rational synthon
`selection presented here, it follo~vs that strategies of rational design
`of co-crystal experimentation are viable.
`
`4.3 Are pharmaceutical co-crystals more or less prone to
`polymorphism than other pharmaceutical phases?
`
`This question ~vill not have a direct ans~ver, because to prove the
`absence of polymorphism is tantamount to "proving the negative".
`But if one considers the argument that compounds have a louver
`degree of self-complementarity than complementarity to a ration-
`ally selected co-crystal former, one might suspect that a compound
`polymorphic in the pure state could display a decreased tendency to
`polymorphism as a co-crystal relative to the pure phase. Support for
`or defeat of this argument ~vill involve significant research. Initial
`indications are that polymorphic substances may provide good
`candidates for co-crystal formation.39a As an example, carbamaze-
`pine can exist as four ~vell characterized polymorphs51 and a
`dihydrate.52 This drug ~vas recently converted to many co-crystals.5
`In terms of assessing polymorphism, one co-crystal of carbamaze-
`pine and saccharin has only displayed one packing arrangement,
`despite testing via HT crystallization in over 2000 experiments.53 In
`contrast, t~vo co-crystal structures of a N,N’-bis(para-bromophe-
`nyl)melamine-diethylbarbital demonstrate ho~v a specific hetero-
`synthon bet~veen the t~vo molecules is robust, but packing of the
`tapes into a crystalline arrangement can lead to t~vo discrete
`polymorphs.54 Hence, there may be opportunity to reduce the
`practical extent of polymorphism of drug compounds specifically
`by co-crystal formation although there may be exceptions.
`
`4.4 What opportunities exist for tuning physico-chemical
`properties by pharmaceutical co-crystal formation?
`
`This is perhaps the most important question, because it is after all
`the complex interplay of form, func